Applicants also claim priority under 35 U.S.C. xc2xa7119(a-d) of Italian patent application no. MI99A 002173, filed Oct. 18, 1999, which is hereby incorporated by reference.
The present invention relates to isoxazolecarboxamide derivatives, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
U.S. Pat. No. 5,403,842, Leonardi et al., and its continuations (U.S. Pat. No. 5,474,994, Leonardi et al. and U.S. Pat. No. 5,605,896, Leonardi et al.) claim heterobicyclic derivatives bearing substituted phenylpiperazines linked to the heterocyclic ring by a variety of spacer groups. Among said derivatives, compound A (Ex. 11) is of particular interest due its high activity and uroselectivity. 
Compound A is endowed with good affinity for the xcex11A adrenoceptor and is able to selectively inhibit contractility of the prostatic urethra in a dog model without substantial effects on blood pressure (Leonardi et al., J. Pharmacol. Exp. Therap., 281:1272-1283, 1997).
N,xcfx89-Aminoalkylamides of 3-phenyl-4-isoxazolecarboxylic acid are known compounds, but prior-art molecules possess quite diverse molecular structures as compared to those claimed in this patent and a completely different pharmacological effect. For example, European patent EP 0573883, Jeschke et al., includes, as a representative compound, 3-(2-chloro-6-fluorophenyl)-N-[3-(2-chlorophenylamino)propyl]-5-methyl-isoxazole-4-carboxamide and other similar derivatives and their claimed therapeutic application is the care of endoparasitoses. European patent EP 0428434, Emonds-Alt et al., claims 3-(2-chlorophenyl)-N-{2-(3,4-dichlorophenyl)-4-[4-(phenylmethyl)-1-piperidinyl]butyl}-5-methylisoxazole-4-carboxamide as substance P antagonists. Neither of these patents claim arylpiperazinyl derivatives active at the xcex11 adrenergic receptor.
The present invention is directed to the structural class of N-(substituted phenyl)-Nxe2x80x2-[xcfx89-(3-substituted phenyl-4-isoxazolecarbonylamino)alkyl]piperazines. The compounds of this class are endowed with enhanced selectivity toward the xcex11 adrenergic receptor (with or without further selectivity for the xcex11A receptor or for both the xcex11A and xcex11D), in particular with respect to the 5-HT1A receptor, and improved in vivo uroselectivity even compared to compound A, with remarkable effects on relaxation of prostatic urethra and very low activity in lowering blood pressure. This activity profile suggests the safer use of the compounds of the invention in the therapy of obstructive syndromes of the lower urinary tract, including benign prostatic hyperplasia (BPH); of lower urinary tract symptoms (LUTS); and neurogenic lower urinary tract dysfunction (NLUTD), without side-effects associated with hypotensive activity.
The invention provides compounds of the general formula I: 
wherein:
R is selected from the group consisting of alkyl, alkoxy, polyfluoroalkoxy, hydroxy and trifluoromethanesulfonyloxy group;
each of R1 and R2 independently is selected from the group consisting of a hydrogen, halogen, polyfluoroalkoxy and alkoxy group;
R3 represents one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl, carboxamido group;
R4 is selected from the group consisting of a hydrogen atom, an alkyl group and an arylalkyl group; and
n is 0, 1 or 2.
The invention also includes the N-oxides and pharmaceutically acceptable salts of these compounds.
Preferred alkyl groups which R and R4 may represent are without limitation lower (C1-4) alkyl groups, most preferably methyl (CH3). Preferred alkoxy groups which R, R1, R2 and R3 may represent without limitation are lower (C1-4) alkoxy groups, most preferably methoxy. Preferred polyfluoroalkoxy groups which R, R1 and R2 may represent are without limitation trifluoromethoxy or 2,2,2-trifluoroethoxy groups. The preferred value for n is 1.
A preferred arylalkyl group that R4 may represent without limitation is phenyl, optionally substituted with one or more substituent selected from the group consisting of hydrogen, halogen, C1-4 alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl and carboxamido group.
A preferred group that R3 may represent without limitation is carboxamido.
Also preferred is where R is selected from the group consisting of alkoxy and hydroxy; R1 is selected from the group consisting of hydrogen and halogen; R2 is selected from the group consisting of hydrogen and halogen; R3 represents one or more substitutents consisting of hydrogen, halogen, alkyl, alkoxy, nitro, amino, acylamino, cyano, alkoxycarbonyl and carboxamido group; R4 is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
Also preferred is where R is selected from a group consisting of alkoxy, alkyl and polyfluoroalkoxy; R1 is selected from the group consisting of hydrogen, halogen and alkoxy; R2 is selected from the group consisting of hydrogen, halogen and alkoxy; R3 represents one or more substitutents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, and amino; R4 is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
Also preferred is where R is selected from the group consisting of alkoxy, alkyl and polyfluoroalkoxy, R1 is halogen; R2 is hydrogen; R3 represents one or more substitutents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy and amino; R4 is selected from the group consisting of hydrogen and alkyl; and n is 0, 1 or 2.
The compounds of the invention include those compounds where, independently, R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from a group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R3 is carboxamido, R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; and n is 0, 1 or 2.
Other compounds within the invention are those compounds with combinations of substituents where, together, R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R1 is selected from the group consisting of hydrogen and fluorine; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R3 is carboxamido; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
Compounds of the invention also include those compounds with combinations of substituents where, together, R1 is selected from the group consisting of hydrogen and fluorine and R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy; or R1 is selected from the group consisting of hydrogen and fluorine and R3 is carboxamido; or R1 is selected from the group consisting of hydrogen and fluorine and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
Also included within the invention are compounds with combinations of substituents where, together, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R3 is carboxamido; or R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R3 is carboxamido and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
The invention also includes compounds having combinations of substituents where, together, R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine and R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine and R3is carboxamido; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine and R4is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R3is carboxamido; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R3 is carboxamido and R4is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
The compounds of the invention also include compounds having combinations of substituents where, together, R1 is selected from the group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R3 is carboxamido; or R1 is selected from the group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R4is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R1 is selected from the group consisting of hydrogen and fluorine, R3is carboxamido and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R3 is carboxamido and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen. For each of these combinations, n is 0, 1, or 2.
Other compounds within the invention are those with combinations of substituents where, together, R1 is selected from the group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R3 is carboxamido and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R3 is carboxamido, and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine, R3 is carboxamido and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy and R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; or R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from the group consisting of hydrogen and fluorine, R2 is selected from the group consisting of hydrogen, chlorine and 2,2,2-trifluoroethoxy and R3 is carboxamido. For each of these combinations, n is 0, 1, or 2.
Still other compounds within the invention are those compounds where together R is selected from the group consisting of methyl, methoxy, 2,2,2,-trifluoroethoxy, hydroxy and trifluoromethanesulfonyloxy, R1 is selected from a group consisting of hydrogen and fluorine, R2 is selected from the group consisting of a hydrogen, chlorine and 2,2,2-trifluoroethoxy, R3 is carboxamido, R4 is selected from the group consisting of methyl, ethyl, 2-phenylethyl, 3-phenylpropyl and hydrogen; and n is 0, 1 or 2.
The invention further provides pharmaceutical compositions comprising a compound of the general formula I or an N-oxide or pharmaceutically acceptable salt of such a compound, in admixture with a pharmaceutically acceptable diluent or carrier. Preferences are as outlined above for the compounds of the invention.
In another aspect, the invention is directed to methods for selectively preventing contractions (including noradrenaline-mediated contractions) of the urethra and lower urinary tract, without substantially affecting blood pressure, by administering one or more selected compounds of the general formula I to a mammal (including a human) in need of such treatment in an amount or amounts effective for the particular use.
In yet another aspect, the invention is directed to methods for blocking xcex11 receptors by exposing said receptors (e.g, by delivery to the environment of said receptors, by addition to an extracellular medium, or by administering to a mammal possessing said receptors) an effective amount of a compound of the invention, in this way relieving diseases associated to overactivity of said receptors.
It is a primary object of the present invention to provide a method of treating BPH which avoids any undue side effects due to acute hypotension (i.e., limited effects on blood pressure).
It is another object of the present invention to provide pharmaceutical compositions comprising isoxazole compounds which are selective xcex11 adrenoceptor antagonists, which compositions are effective for the treatment of BPH optionally including a carrier or diluent.
It is another object of the present invention to provide a method of treating BPH using isoxazole compounds which are selective xcex11 adrenoceptor antagonists.
Another aspect of the invention is the use of new compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, reducing sympathetically-mediated pain and the treatment of cardiac arrhythmia and erectile dysfunction, as well as LUTS and NLUTD.
An object of the present invention is to provide a method of preventing contractions of the urethra and lower urinary tract comprising administering to a mammal including a human in need of such treatment an effective amount of compounds of the present invention and/or pharmaceutical compositions comprising compounds of the present invention.
A further object of the present invention is a method of administration of compounds of the present invention or pharmaceutical compositions comprising compounds of the present invention to mammals including humans which causes very limited effects on the blood pressure of said mammal.
As used herein, xe2x80x9climited effect on blood pressurexe2x80x9d and xe2x80x9cwithout substantial effect on blood pressurexe2x80x9d are defined as effects on blood pressure that are without clinical significance. In experimental animals, xe2x80x9climitedxe2x80x9d and xe2x80x9cwithout substantialxe2x80x9d effects on blood pressure are defined as lowering blood pressure by about 10% or less, compared to control animals. In humans, xe2x80x9climitedxe2x80x9d and xe2x80x9cwithout substantialxe2x80x9d effects on blood pressure are defined as effects wherein diastolic blood pressure is reduced by less than about 5 mm Hg.
A further object of the present invention is a method for blocking xcex11 adrenergic receptors comprising releasing in the environment of said receptors compounds of the present inventions or pharmaceutical compositions of the present invention to relieve diseases associated with overactivity of said receptor.
A further object of the present invention is the release of compounds of the present invention or pharmaceutical compositions containing compounds of the present invention in the environment of xcex11 adrenergic receptors wherein said release is effected by administering compounds of the present invention or pharmaceutical compositions containing compounds of the present invention to a mammal including a human possessing said receptors.
A further object of the present invention is the method of treatment of a patient suffering from benign prostatic hyperplasia, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from excessive intraocular pressure, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from cardiac arrhythmia, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from erectile dysfunction, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method of treatment of a patient suffering from sexual dysfunction, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method for inhibiting cholesterol biosynthesis, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
A further object of the present invention is the method for reducing sympathetically mediated pain, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment.
It is understood that xe2x80x9csympathetically-mediatedxe2x80x9d is defined as any physiological sensation, condition or response that depends upon any component of the sympathetic nervous system, can be modulated by the action of any component of the sympathetic nervous system, or can be affected by treatment of any component of the sympathetic nervous system.
A further object of the present invention is the method for the treatment of lower urinary tract symptoms (LUTS), which include but are not limited to filling symptoms, urgency, incontinence and nocturia, as well as voiding problems such as weak stream, hesitance, intermittency, incomplete bladder emptying and abdominal straining, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a patient in need of such treatment, optionally farther comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine.
A further object of the present invention is the method for the treatment of neurogenic lower urinary tract dysfunction (NLUTD), the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to the patient, optionally further comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine.
A further object of the present invention is the treatment of LUTS in females which include but are not limited to filling symptoms, urgency, incontinence, and nocturia as well as voiding problems such as weak stream, hesitance, intermittency, incomplete bladder emptying, and abdominal straining, the method comprising administering an effective amount of a compound of the present invention or a pharmaceutical composition containing a compound of the present invention to a woman in need of such treatment, optionally further comprising the inclusion of an anticholinergic compound which may be selected from the group consisting of tolterodine, oxybutinin, darifenacin, alvameline and temiverine.
For all uses and methods described herein, preferences are as outlined above for the compounds of the invention.
Other features and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims.
All patents, patent applications, and literature references cited in this application are incorporated by reference in their entirety.
The adrenergic antagonistic activity of the compounds of the invention renders them useful as agents acting on body tissues particularly rich in xcex11 adrenergic receptors (such as prostate and urethra). Accordingly, anti-adrenergic compounds within the invention, established as such on the basis of their receptor binding profile, can be useful therapeutic agents for the treatment, for example, of micturition problems associated with obstructive disorders of the lower urinary tract, including but not limited to benign prostatic hyperplasia (BPH).
BPH is a progressive condition, which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urinary stream and hesitancy or delay in starting urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the ageing male population. BPH is observed in approximately 70% of males over the age of 70. Currently, the worldwide stated method of choice for treating. BPH is surgery. A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
xcex1-Adrenergic receptors (McGrath et. al., Med. Res. Rev., 9:407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important targets for controlling many physiological functions and thus represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin, tamsulosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter noradrenaline, and antagonists (phenoxybenzamine and prazosin, terazosin, alfuzosin, doxazosin and tamsulosin are antagonists), which act to block the effects of noreadrenaline. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
The above reported agonists are selective for the xcex12 adrenergic receptor whereas most antagonists are selective for the xcex11 adrenoceptor, with the exception of tamsulosin which shows a comparable affinity also for the 5-HT1A receptor. Many of the cited xcex11 antagonists are currently used for the therapy of BPH but, due to their poor uroselectivity, they are liable to cause cardiovascular side effects.
Recent pharmacological, biochemical and radioligand-binding studies evidenced three different xcex11-receptor subtypes with a high affinity for prazosin, namely xcex11Axe2x88x92 (xcex11axe2x88x92), xcex11Bxe2x88x92 (xcex11bxe2x88x92) and xcex11Dxe2x88x92 (xcex11dxe2x88x92), with lower case subscripts being used for recombinant receptors and upper case subscripts for receptors in native tissues (Hieble et al., Pharmacol. Rev., 47:267-270, 1995). In functional studies xcex11 receptors with a low affinity for prazosin have also been identified and termed xcex11L receptors (Flavahan et al., Trends Pharmacol. Sci., 7:347-349, 1986; Muramatsu et al., Pharmacol. Comm., 6:23-28, 1995).
Several studies have demonstrated the presence of these xcex11-adrenergic-receptor subtypes in the lower-urinary-tract tissues (Andersson K. E., 4th International Consultation in Benign Prostatic Hyperplasia (BPH)xe2x80x9d, Paris, Jul. 2-5, 1997, pages 601-609).
Several studies have shown that the human prostate receives innervation from both the sympathetic and parasympathetic nervous systems.
The adrenergic nerves are considered responsible for prostatic smooth-muscle tone by releasing noradrenaline, stimulating contraction-mediating xcex11-adrenergic receptors. Approximately 50% of the total urethral pressure in BPH patients may be due to xcex11-adrenoceptor-mediated muscle tone. Functional studies have indicated the occurrence of important adrenoceptor functions in prostatic adenomatous and capsular tissue. Clinical studies with the prototypical xcex11-adrenoceptor-selective antagonist, prazosin, enforced the key role of xcex11 adrenoceptors in the control of prostatic smooth-muscle tone. This was also confirmed in the laboratory by studies showing that, although both xcex11 and xcex12 adrenoceptors can be identified within the human prostate, contractile properties are mediated primarily by xcex11 adrenoceptors. Many clinical investigations have confirmed that xcex11-adrenoceptor blockade relieves lower-urinary-tract symptoms (LUTS), both of irritative and obstructive type, in patients with BPH.
Lower urinary tract symptoms (LUTS) also develop in women as they age. As in men, LUTS in women includes both filling symptoms such as urgency, incontinence, and nocturia, and voiding symptoms, such as weak stream, hesitancy, intermittency, incomplete bladder emptying and abdominal straining. That both men and women experience a similar high prevalence of filling and voiding LUTS suggests that at least part of the underlying etiology may be identical. In a recent study, an xcex11-antagonist was reported to reduce LUTS in women to a greater extent than an anticholinergic (Serels, S. and Stein, M., Neurology and Urodynamics 17: 31-36, 1998). The authors concluded that there appeared to be a role for xcex11-antagonists in treating LUTS in women. The possible mechanisms implicated to explain these results are: a) dysfunction of the bladder neck and urethra, causing functional outlet obstruction, analogous to BPH-induced outlet obstruction, with secondary detrusor overactivity; and b) increased xcex11-adrenoreceptor activity in the detrusor, causing frequency and urgency. On these bases, xcex11-antagonists are used in clinical practice to treat LUTS in women (Fitzpatrick, International British J. Urol. 85, Supp. 2: 1-5, 2000; Kakizaki, M. et al., Brit. J. Urol. International 85, Supp. 2: 25-30, 2000). The results of Serels also indicate that the combined administration of xcex11-antagonists and anticholinergics can have improved efficacy in treatment of LUTS, as suggested by Fitzpatrick (International British J. Urol. 85, Supp. 2: 1-5, 2000).
Another possible use of xcex11-antagonists is the management of neurogenic lower urinary tract dysfunction (NLUTD), as can be caused by neurological disease or trauma. NLUTD may lead to debilitating symptoms and serious complications, including increased urinary frequency, incontinence, voiding difficulty, recurrent upper urinary tract infections, and upper urinary tract deterioration. Management of NLUTD is indicated to preserve renal function and avoid urological complications. Administration of xcex11-antagonists may benefit patients with NLUTD by facilitating urine storage by alleviating high detrusor pressure during bladder filling, which is evidenced by poor bladder compliance and detrusor hyperreflexia. In both animal models and patients with spinal cord injury resistant to anticholinergics, xcex11-antagonists improved bladder compliance. (Kakizaki, M. et al., Brit. J. Urol International 85, Supp.2: 25-30, 2000); Sundin, T. et al., Invest Urol. 14: 322-328, 1977; McGuire et al., Neurology and Urodynamics 4: 139-142, 1985; Swierzewski, S. J. etal., J. Urol. 151: 951-954, 1994).
Two distinct xcex11-adrenoceptor subtypes have been suggested to be present in the human prostate, one (xcex11H) with high and one (xcex11L) with low affinity for prazosin. All three high-affinity xcex11-adrenoceptor subtypes found in molecular cloning studies have been identified in prostatic stromal tissue. The xcex11a subtype was found to be the dominant, representing about 60-85% of the xcex11-adrenoceptor population. Recent findings suggest that there may be differences in subtype populations between normal and hyperplastic prostates, the ratios between the subtypes xcex11a:xcex11b:xcex11d being 85:1:14 in BPH tissue and 63:6:31 in non-BPH tissue.
The xcex11A adrenoceptor was reported to mediate the contractile response of the human prostate in vitro. Ford et al. (Br. J. Pharmacol., 114:24 P, 1995) found that the xcex11A adrenoceptor may not mediate contractile responses to noradrenaline, and suggested as a candidate the xcex11L adrenoceptor. Findings by Kenny et al. (Br. J. Pharmacol., 118:871-878, 1996) support the view that the xcex11L adrenoceptor, which appears to share many of the characteristics of an xcex11A adrenoceptor, mediates the contractile response of the human prostate.
In the female urethra, mRNA for the xcex11 subtype was predominant and autoradiography confirmed the predominance of the xcex11A adrenoceptor (Andersson, K. E., Brit. J. Urol. Intl. 85, Supp. 2: 12-18, 2000). The xcex11A and xcex11D subtypes are reported to be present in the human detrusor, with the latter subtype predominant (Malloy B. et al., J. Urol. 160: 937-943, 1998). Accordingly, the evidence that xcex11 adrenoreceptor antagonists are useful in treating lower urinary tract symptoms of both prostatic and non-prostatic origin in both males and females can be used to support the usefulness of the compounds of the present invention in treating such symptoms regardless of whether they are of obstructive origin or not and regardless of the sex of the patient.
On the other hand, it has also been suggested that the xcex11A and xcex11L adrenoceptors may represent distinct pharmacological forms of the same receptor.
The affinity of the compounds of the invention for each receptor can be assessed by receptor binding assays, for example as follows:
(1) xcex11-adrenergic-receptor subtypes: using the specific ligand 3H-prazosin, according to Testa R. et al., Pharmacol. Comm. 6: 79-86, 1995; Cotecchia S. et al., Proc. Natl. Acad. Sci. USA, 85: 7159-7163, 1988; Furchgott R. E., Handbook of Experimental Pharmacologyxe2x80x94New Series, 283-335, 1972; Michel M. C. et al., Brit. J. Pharmacol. 111: 533-538, 1994; Schwinn D. A. et al., J. Biol. Chem 265: 8183-8189, 1990; Testa R. et al., Eur. J. Pharmacol. 249: 307-315, 1993.
(2) 5HT1A-serotonergic receptor: using the specific ligand 3H-8-OH-DPAT according to Fargin et al., Nature 335: 358-360, 1988; Kobilka B. K. et al., Nature 329: 75-79, 1987; Cullen B. R., Meth. Enzym 152: 684-704, 1987; Gozlan, H. et al., J. Receptor Res. 7: 195-221, 1987).
The xcex11L-adrenergic receptor is not yet cloned and, therefore, the functional affinity of the compounds of the invention for this subtype can be assessed by using an isolated organ preparation as reported by Testa et al., J. Pharmacol. Exp. Ther. 281: 1284-1293, 1997; Oshita, M. et al., Br. J. Pharmacol. 108: 1071-1076, 1993.
In vitro testing of the compounds of this invention on the above receptors is described in Examples 37 and 38 below.
The drugs having xcex11-adrenergic antagonistic activity currently used for the symptomatic therapy of BPH are poorly subtype selective and subject to cause relevant side effects due to their hypotensive activity.
Thus there is a need for selective xcex11-antagonists which do not subject the BPH patient to the side effects, especially the cardiovascular side effects of said treatment. The very high uroselectivity of the compounds of this invention has been tested in the dog model described in Example 39, where their efficacy in antagonizing the contractions of prostatic urethra in the presence of very limited effects on blood pressure has been shown, in comparison to compound A and to another well-known xcex11-antagonist, prazosin.
The compounds according to the invention may generally be prepared as follows. 
Direct condensation of compounds 1, 4-carboxy-3-aryl isoxazole derivatives, with the xcfx89-aminoalkyl derivatives 2 (Scheme 1) leads to the compounds of the invention. The condensation can be carried out in presence of a condensing agent (e.g., dicyclohexylcarbodiimide or diethyl cyanophosphonate) optionally in the presence of a promoting agent (e.g., N-hydroxysuccinimide, 4-dimethylaminopyridine or N,Nxe2x80x2-carbonyldiimidazole) in an aprotic or chlorinated solvent (e.g., dimethylformamide or chloroform) at xe2x88x9210/140xc2x0 C. (Albertson, Org. React., 12:205-218, 1962; Doherty et al., J. Med. Chem., 35:2-14, 1992; Ishihara et al., Chem. Pharm. Bull., 39:3236-3243, 1991). In some cases the activated intermediate esters or amides (such as O-(N-succinimidyl)esters or acyl imidazolides) can be isolated and further reacted with 2 to be transformed into the corresponding amides (I) in an aprotic or chlorinated solvent at 10/100xc2x0 C. This kind of condensation is well illustrated in the examples. Another activated intermediate which can be used is the mixed anhydride of 1, obtainable by reacting 1 with an alkyl chloroformate in presence of a tertiary amine (e.g., triethylamine or N-methylmorpholine), then reacted with 2 at 0-80xc2x0 C.; optionally a promoting agent (e.g., 1-hydroxypiperidine) may be added before the amine addition (Albertson, Org. React., 12:157, 1962).
Alternatively, the condensation can be carried out without a solvent at 150-220xc2x0 C. (Mitchell et al., J. Am. Chem. Soc., 53:1879, 1931) or in high-boiling ethereal solvents (e.g., diglyme).
The condensation can be also performed through preparation and optional isolation of reactive derivatives of 1, such as acyl halides. Formation of acyl halides of compounds of formula 1 and reactions with amines 2 to form amides is well documented in the literature and known to people skilled in the art.
Also less reactive derivatives of 1 can be used, such as alkyl esters, which, in turn, can be converted into 1 in the presence of a condensing agent (e.g., trimethylaluminum) in an aprotic and/or a chlorinated solvent (e.g., hexane, dichloromethane) at xe2x88x9210/80xc2x0 C., or without solvents at 80-180xc2x0 C., (Weinreb et al., Tetrahedron Lett., 4171, 1977; Lipton et al., Org. Synth., 59:49, 1979).
By the same methods of condensation reported above and using H2NCH2(CH2)nCH2X (with X=halogen or OH) as a reagent, 1 can be transformed into 3. In the case of X=OH, the alcoholic group is then converted into a suitable leaving group by methods well known to those skilled in the art. Compounds 3 (with X=leaving group such as halogen or aryl/alkylsulphonyloxy group) can be subsequently reacted with an appropriate phenylpiperazine 4 bearing the desired phenyl group. The nucleophilic substitution is carried out preferably, but not necessarily at a temperature within the range of 20-200xc2x0 C. in a polar solvent such as dimethylformamide, acetonitrile or methanol, or without any solvent, usually in the presence of a base such as potassium carbonate. See also Gibson""s chapter in Patai: xe2x80x9cThe Chemistry of the Amino Groupxe2x80x9d, p. 45, Wiley Int. Sci., N.Y. (1968).
The preparation of compounds 1 which are not commercially available is disclosed in the literature and is well known to those skilled in the art and is usually carried out performing 1,3-dipolar cycloaddition reactions on benzohydroxamoyl halides (usually prepared by halogenation reaction on properly substituted benzaldoximes with elemental halides or alkali hypohalogenides or N-chloro-(or bromo)succinimide) with xcex2-ketoesters or alkyl xcex2-aminoacrylates (R4=H) or alkyl propiolates in alkaline condition in a proper solvent (e.g., dimethylformamide, ethanol, diethyl ether, chlorinated solvents at a temperature in the range between xe2x88x9220xc2x0 C. to reflux, usually carrying out the reactions at 20-30xc2x0 C.). (Scheme 2) See J. Chem. Soc. 19063, 5838-5845 and 5845-5854; J. Am. Chem. Soc. 1985, 107, 2721-2730, J. Agric. Food Chem. 1995, 43, 219-228; U.S. Pat. No. 4,144,047. 
Variation of the R4 substitution can be obtained by using properly substituted xcex2-ketoesters or alkyl propiolates or by reacting the lithium carbanion of the methyl derivatives 1 (R4=CH3) with various electrophiles in aprotic solvents such as tetrahydrofuran, diethyl ether, benzene, toluene or others at a temperature between xe2x88x9278xc2x0 C. and the temperature of reflux of the solvent (J. Org. Chem. 1985, 50, 5660-5666; J. Med. Chem. 1988, 31, 473-476; J. Med. Chem. 1990, 33, 2255-2259). The carboxylic functionality can be protected or not.
The preparation of compounds 2 is disclosed in the literature and is well known to those skilled in the art, and includes nucleophilic substitution of a phenylpiperazine 4 on a N-(xcfx89-haloalkyl)phthalimide or a proper xcfx89-haloalkylnitrile or amide by the method illustrated above for the condensation of compounds 3 and 4 or by addition of a xcex1,xcex2-unsaturated alkylnitrile or amide in a suitable solvent (e.g., acetonitrile, dimethylformamide, a chlorinated solvent or other aprotic polar solvent) at a temperature between 0xc2x0 C. and the reflux temperature of the solvent. The following standard phthalimido-group deprotection and the reduction of the amido or cyano group provide compounds 2.
The compounds I where R is a trifluoromethanesulphonyloxy group can be synthesised starting from compounds I where R is a hydroxy group by known procedures that include the use of trifluoromethanesulphonic anhydride or N-phenyltrifluoromethanesulphonimide in aprotic solvents such as, for example, 1,2-dichloroethane or other chlorinated solvents, toluene at a temperature in the range between xe2x88x9220xc2x0 C. and the reflux temperature of the solvent (Hendickson et al., Tetrahedron Letters, 4607, 1973).
The N-oxides of compounds I may be synthesised by simple oxidation procedures known to those skilled in the art. The oxidation procedure described by Brougham, Synthesis, 1015-1017, 1987, allows differentiation of the two nitrogen atoms of the piperazine ring, permitting both the N-oxides and the N,Nxe2x80x2-dioxide to be obtained.
The preparation of the phenylpiperazines 4, not yet known in the literature, is very well documented in the experimental part and uses synthetic procedures very well known to those skilled in the art, which comprise the synthesis of the proper aniline through standard reactions and the subsequent cyclization with bis-(2-chloroethylamine) to afford the piperazine following the method of Prelog et al., Collect. Czech. Chem. Comm., 5:497-502, 1933 or its variations (Elworthy, J. Med. Chem., 40:2674-2687, 1997).
Representative examples of the compounds of the invention are, with no intention to limit:
3-phenyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
3-phenyl-N-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
3-phenyl-N-{3-[4-(5-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
3-phenyl-N-{3-[4-(5-fluoro-2-hydroxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-methyl-3-phenyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-methyl-3-phenyl-N-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-methyl-3-phenyl-N-{3-[4-(5-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-methyl-3-phenyl-N-{3-[4-(2-methoxy-4-fluorophenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-methyl-3-phenyl-N-{3-[4-(2-hydroxy-4-fluorophenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-ethyl-3-phenyl-N-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-ethyl-3-phenyl-N-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide;
5-ethyl-3-phenyl-N-{3-[4-(5-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl}isoxazole-4-carboxamide; and
5-ethyl-3-phenyl-N-{(3-[4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl)}isoxazole-4-carboxamide.